PROJECT SUMMARY Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. KRAS is a major oncogenic driver of this disease and found in ~ 30% of all NSCLCs. Unfortunately, efforts to develop drugs that target mutant KRAS proteins have largely been unsuccessful, since both single agent inhibition of effector pathways downstream of KRAS or combinations have proven to be ineffective. Thus, developing novel therapies for KRAS-driven NSCLC remains an area with a critical unmet need. The overarching goal of this proposal is to dissect the mechanistic underpinning of how genetic ablation of CRAF induces regression of KRAS-driven NSCLC. We have generated a KRAS-driven, human NSCLC cell line with inducible CRAF expression that undergoes apoptosis upon CRAF knockdown. This proposal utilizes this system, along with biochemical and immunological techniques, to 1) identify the domain(s) of CRAF responsible for mediating tumor regression, 2) determine the downstream effectors necessary for tumor regression, and 3) characterize the changes within the tumor microenvironment upon CRAF loss. Improved mechanistic understanding of this phenomenon and successful execution of these aims will lead to novel strategies for targeting KRAS-driven lung cancers, either as monotherapy or rationally-designed combination therapy, as well as potential biomarkers predictive of response. Dr. Victoria Wang is mentored by Dr. Frank McCormick, a world expert in RAS signaling, and will also benefit from an advisory committee comprised of Dr. Dean Sheppard, Dr. David Carbone, Dr. Matthew Krummel, and Dr. Shiva Malek, who will collectively provide mentorship, collaboration and expertise in cancer biology, signaling, immunology, and lung cancer translational research. Dr. Wang has also formulated a comprehensive 5-year training plan that will leverage the outstanding resources available at UCSF (ranking second in NIH funding among all institutions), incorporating laboratory training, didactic coursework, scientific meetings and professional development opportunities that will assist her in achieving her scientific and career goals of developing into an independent, translational lung cancer investigator.